Abstract

There is a striking paradox in the literature supporting high-profile measures to
reduce ventilator-associated pneumonia (VAP): many studies show significant reductions
in VAP rates but almost none show any impact on patients' duration of mechanical ventilation,
length of stay in the intensive care unit and hospital, or mortality. The paradox
is largely attributable to lack of specificity in the VAP definition. The clinical
and microbiological criteria for VAP capture a population of patients with an array
of conditions that range from serious to benign. Many of the benign events are manifestations
of bacterial colonization superimposed upon pulmonary edema, atelectasis, or other
non-infectious processes. VAP prevention measures that work by decreasing bacterial
colonization preferentially lower the frequency of these mislabelled, more benign
events. In addition, misclassification obscures detection of an impact of prevention
measures on bona fide pneumonias. Together, these effects create the possibility of
the paradox where a prevention measure may have a large impact on VAP rates but minimal
impact on patients' outcomes. The paradox makes changes in VAP rates alone an unreliable
measure of whether VAP prevention measures are truly beneficial to patients and behooves
us to measure their impact on patient outcomes before advocating their adoption.

The paradox

Hospitals around the world are striving to reduce their rates of ventilator-associated
pneumonia (VAP) in order to improve patient outcomes and minimize costs. Professional
societies, legislators, quality improvement advocates, and medical product manufacturers
are promoting an increasing array of interventions to reduce VAP rates. These include
regular oral care, elevation of the head of the bed, continuous aspiration of subglottic
secretions, silver-coated endotracheal tubes, and many other initiatives. Some jurisdictions
now mandate hospitals to report adherence with a subset of these 'process measures'.
Review of the literature supporting these interventions, however, reveals a striking
paradox: each of these strategies dramatically reduces VAP rates but almost none has
any impact on patients' duration of mechanical ventilation, hospital length of stay,
or mortality (Table 1).

Regular oral care with chlorhexidine, for example, reduces VAP rates by up to 37%
to 66% but has no impact on duration of mechanical ventilation, intensive care unit
(ICU) or hospital length of stay, or mortality [1-4]. Likewise, elevation of the head reduces the VAP rate by 78% [5], continuous aspiration of subglottic secretions reduces VAP rates by 50% to 55% [6,7], and silver-coated endotracheal tubes decrease VAP rates by 36% [8]. None of these investigations, though, showed an impact on patients' outcomes. Many
of these studies were not primarily powered to detect a difference in length of stay
or mortality, but it is striking that they did not even show trends toward improvements
in these outcomes regardless of whether considered alone or in meta-analyses that
included thousands of patients [4,9,10]. The failure of these studies to detect an impact on patient outcomes is conspicuous
since the balance of research does show that VAP doubles the risk of dying and increases
intensive care length of stay by a mean of 6 days [11].

The explanation

The source of this paradox lies in the ambiguity and inaccuracy inherent in VAP diagnosis.
VAP is typically defined as the presence of fever, abnormal white blood cell count,
purulent sputum, and new radiographic infiltrates. On intensive investigation, however,
only a fraction of patients with these signs truly have histological pneumonia [12]. Instead, up to two thirds of people who fulfill this definition have one or more
alternative conditions that range from relatively benign, such as atelectasis and
tracheobronchitis, to severe, such as acute respiratory distress syndrome or pulmonary
infarction [13,14].

The addition of microbiological criteria does little to improve accuracy. Many studies
define VAP as the presence of greater than 1,000 colony-forming units per milliliter
on culture of bronchoalveolar lavage fluid. This definition is attractive because
it is objective, but unfortunately it is no more accurate than clinical criteria alone
[15]. The sensitivity and specificity of this definition relative to a histological gold
standard are only 50%-70% and 40%-95%, respectively [16-19]. False positives are due to contamination of the lavage specimen by bacteria colonizing
the patient's endotracheal tube and upper airway. This effect is particularly marked
in patients with prolonged ventilation. False negatives arise from the failure to
sample the correct lung segment, insufficient bacterial growth to cross the quantitative
threshold, and damping of bacterial growth by prior antibiotic exposure.

Much of VAP misdiagnosis stems from bacterial colonization superimposed upon non-infectious
pulmonary processes such as fluid shifts, barotrauma, atelectasis, inflammatory reactions,
and exacerbations of patients' underlying lung disease. These factors wax and wane
in ways that are difficult to discern at the bedside, leading to the transient appearance
of clinical syndromes suggestive of VAP. As often as not, these processes spontaneously
resolve in short order without definitive therapy. Clinical trials for early empiric
treatment of suspected VAP followed by reassessment 48 to 72 hours later hint at this
process. In many patients, the VAP syndrome is no longer present on reassessment and
antibiotics can safely be stopped without discernible impact on patient outcomes [20-22].

Mislabelling benign events as VAP creates bias if prevention measures preferentially
affect the more benign disorders over the more serious disorders present within the
spectrum of conditions that look like VAP. This is particularly likely in studies
that use a microbiological definition of VAP to assess interventions that work by
decreasing bacterial colonization of the endotracheal tube. For example, the NASCENT
(North American Silver-Coated Endotracheal Tube) study of silver-coated endotracheal
tubes compared with conventional endotracheal tubes found a statistically significant
36% reduction in microbiologically confirmed VAP yet no difference in the rate of
physician-suspected VAP (26% versus 31%, P = 0.39) or patients with radiographic infiltrates and suggestive clinical signs (53%
versus 56%, P = 0.74) [8]. This discrepancy between rates of microbiologically defined VAP versus clinically
defined VAP suggests that silver-coated tubes preferentially decrease colonization
rather than infection. This is further borne out by identical durations of mechanical
ventilation, ICU stay, hospital stay, and mortality between patients with silver-coated
versus conventional tubes. Other interventions that decrease microbial colonization,
such as oral chlorhexidine and continuous aspiration of subglottic secretions, might
also be subject to this bias.

Mislabelling benign events as VAP further contributes to the paradox by obscuring
faint but true signals from bona fide pneumonias. Some interventions designed to prevent
VAP may well reduce the frequency of bona fide pneumonias (and truly improve outcomes
for this subset of patients), but the plethora of alternative conditions captured
by the VAP definition dilute the signal coming from the subset of patients with true
pneumonias. Generally low event rates in both the intervention and control groups
of many studies compound the challenge of detecting significant impacts on outcomes.
These effects may also explain some of the conflicting results in studies evaluating
the attributable mortality of VAP: the failure of some studies to detect an impact
on mortality [23-26] despite a statistically significant impact in other studies [27-29] and on meta-analysis [11] may be due to damping of the 'true' VAP morbidity signal by misclassifying relatively
benign conditions as VAP. Alternatively, VAP may be more of a marker for severity
of illness in intubated patients rather than an independent source of morbidity in
and of itself. Either way, the failure of multiple clinical trials to detect an impact
of VAP prevention measures on patient outcomes suggests that the net benefit of these
interventions on the population level is small.

The implication

The near impossibility of accurate VAP diagnosis compels us to exert great caution
when interpreting trial data and hospital surveillance data showing decreases in VAP
rates. Lower rates in the intervention arm of clinical trials may reflect disproportionate
decreases in benign mimickers of VAP rather than VAP itself. Similarly, observational
reports of markedly reduced VAP rates in some hospitals may reflect measurement artefact
more than true reductions in serious disease [14]. Before advocating their adoption, we need to see that new interventions and quality
improvement programs impact meaningful outcomes rather than just VAP rates.

Likewise, legislators considering mandatory reporting of VAP prevention process measures
should consider their impact on outcomes before compelling implementation. Due to
the inaccuracy and ambiguity in surveillance definitions, many jurisdictions have
shied away from requiring VAP reporting [14,30]. It will be a great irony if these jurisdictions now compel hospitals to report VAP
prevention process measures validated by studies that used the same imperfect VAP
definitions to prove their value yet failed to show any impact on patient outcomes.

Clinicians and patients can take heart that some interventions have been shown to
improve hard outcomes and do merit adoption. Selective oropharyngeal decontamination
reduces ICU patients' mortality [31]. Likewise, daily sedative interruptions and daily assessments of readiness to extubate
consistently reduce patients' duration of mechanical ventilation and possibly lower
mortality (Table 2) [32-38]. Other VAP prevention measures may decrease antibiotic usage [39,40] but this outcome has not yet been widely studied.

There is also tentative evidence that combining interventions into bundles may impact
patient outcomes even when the component interventions alone do not. Ventilator bundles
typically include elevating the head of the bed, stress ulcer prophylaxis, thromboembolism
prophylaxis, and a daily weaning assessment. None of these measures in isolation has
been shown to decrease patients' length of stay, yet three centers implementing these
measures as a bundle reported shorter ICU lengths of stay [41-43] and a fourth center found shorter hospital length of stay [44] compared with historical rates. These studies, while promising, need to be interpreted
with great caution since they suffer many methodological limitations, including the
use of historical rather than concurrent controls [45].

For too long, we have accepted VAP as a surrogate marker for the outcomes we really
care about, namely patients' duration of mechanical ventilation, hospital length of
stay, and mortality. The disparity between prevention measures' impact on VAP rates
and their lack of impact on patient outcomes underscores the inadequacy of VAP as
a surrogate marker. We need to directly assess the impact of VAP prevention measures
on patient outcomes before advocating or compelling their adoption.